Endosidin2 targets conserved exocyst complex subunit EXO70 to inhibit exocytosis
Endosidin2 targets conserved exocyst complex subunit EXO70 to inhibit exocytosis
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DOI：
10.1073/pnas.1521248112
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发表时间：
2016-01-05
影响因子：
11.1
通讯作者：
Raikhel, Natasha V.
中科院分区：
文献类型：
--
作者：
Zhang, Chunhua;Brown, Michelle Q.;Raikhel, Natasha V.
胞囊复合体调节胞吐的最后步骤，这是跨王国生物体所必需的。在人类中，它的功能障碍与几种重要疾病有关，如糖尿病和癌症进展。在拟南芥等遗传易感生物中，利用突变体对进化保守的囊泡相关过程进行动态调控的研究受到致死率或表型严重程度的限制。我们发现，小分子内sidin2 （ES2）与外囊复合物的EXO70 （70 kDa的外囊成分）亚基结合，抑制植物和人类细胞的外胞分泌和内体循环，增强植物液泡运输。具有c端截断的EXO70蛋白导致显性ES2抗性，揭示了该蛋白的N端可能具有不同的调节作用。这项研究不仅为研究胞吐调节提供了有价值的工具，而且为治疗人类疾病的药物提供了潜在的新靶点。
The exocyst complex regulates the last steps of exocytosis, which is essential to organisms across kingdoms. In humans, its dysfunction is correlated with several significant diseases, such as diabetes and cancer progression. Investigation of the dynamic regulation of the evolutionarily conserved exocyst-related processes using mutants in genetically tractable organisms such as Arabidopsis thaliana is limited by the lethality or the severity of phenotypes. We discovered that the small molecule Endosidin2 (ES2) binds to the EXO70 (exocyst component of 70 kDa) subunit of the exocyst complex, resulting in inhibition of exocytosis and endosomal recycling in both plant and human cells and enhancement of plant vacuolar trafficking. An EXO70 protein with a C-terminal truncation results in dominant ES2 resistance, uncovering possible distinct regulatory roles for the N terminus of the protein. This study not only provides a valuable tool in studying exocytosis regulation but also offers a potentially new target for drugs aimed at addressing human disease.